In 1656, Louis XIV charged the architect Libéral Bruant to build a hospital on the location of the factory, founding the Hospice de la Salpêtrière. The building was expanded in 1684.

By the eve of the Revolution, it had become the world's largest hospital, with a capacity of 10,000 patients plus 300 prisoners, largely prostitutes swept from the streets of Paris. From La Salpêtrière they were paired with convicts and forcibly expatriated to New France.

During the September massacres of 1792, the Salpêtrière was stormed on the night of 3/4 September by a mob from the impoverished working-class district of the Faubourg Saint-Marcel, with the avowed intention of releasing the detained street-girls; 134 of the prostitutes were released; twenty-five madwomen were less fortunate and were dragged, some still in their chains, into the streets and murdered.[3]Madame Roland, a Girondin supporter of the Revolution in its first liberalising stages, recorded in her Memoirs that the Revolution "has been stained by villains and become hideous".[4]

In the first half of the 19th century, the first humanitarian reforms in the treatment of the violently insane were initiated here by Philippe Pinel, friend of the Encyclopédistes; his sculptural monument stands before the main entrance in Place Marie-Curie, Boulevard de L'Hôpital. Later, when Dr. Jean-Martin Charcot took over the department, the Salpêtrière became known as a psychiatric centre. Charcot is often credited as the founder of modern neurology. His teaching activities on the Salpêtrière's wards helped to elucidate the natural history and pathophysiology of many human illnesses including neurosyphilis, epilepsy, and stroke. Students came from all over Europe to listen to Charcot's lectures. Among them was a young Sigmund Freud.

The Hôpital de la Pitié, founded about 1612, was moved next to the Salpêtrière in 1911 and fused with it in 1964 to form the Groupe Hospitalier Pitié-Salpêtrière. The Pitié-Salpêtrière is now a general teaching hospital with departments focusing on most major medical specialities.

Chapelle de la Salpêtrière (Hospital Chapel), at n° 47 Boulevard de l'Hôpital is one of the masterpieces of Libéral Bruant, architect of Les Invalides. It was built around 1675, on the model of a Greek cross and has four central chapels each capable of holding a congregation of some 1,000 people. Its central octagonal cupola is illuminated by picture windows in circular arcs.

In the place in front of the main entrance to the Hospital, there is a large bronze monument to Philippe Pinel, who was chief physician of the Hospice from 1795 to his death in 1826. The Salpêtrière was, at the time, like a large village, with seven thousand elderly indigent and ailing women, an entrenched bureaucracy, a teeming market and huge infirmaries. Pinel created an inoculation clinic in his service at the Salpêtrière in 1799 and the first vaccination in Paris was given there in April 1800.